The mission of our Perimenopause in Brain Aging and Alzheimer's Disease Program Project is to discover biological transformations in brain that occur during the perimenopausal transition that lead to endophenotypes predictive of risk for Alzheimer's disease (AD). Our goals are to identify the mechanisms by which these transformations occur and to translate these discoveries into strategies to prevent conversion to an at-Alzheimer's-risk phenotype. Each year ~1.5 million American women enter into the perimenopause, a neuroendocrine transition state unique to the female. AD has a protracted preclinical phase that suggests that events early in the aging process can initiate vulnerability t late onset AD. The greatest risk factors for Alzheimer's disease are age, the APOE4 genotype4 and female sex. The proposed program of research builds on our discovery of the perimenopausal bioenergetic transition in brain and its predictive association with cognitive decline in postmenopausal women to investigate the impact of the APOE4 allele on this uniquely female aging transition. We hypothesize that the APOE4 genotype represents the first of three strikes to increase the risk for AD, with aging being the second, and the perimenopausal bioenergetic transition being the third and final strike that initiates risk of developing an at-AD-risk endophenotype in women. We propose that the APOE4 allele accelerates and magnifies the perimenopausal bioenergetic crisis in brain to accelerate and amplify the risk of AD. An interdisciplinary team with deep and broad expertise in aging and AD have created an integrated set of three Projects, supported by three cores, that address common hypotheses and program-wide aims at basic, clinical and population levels of analysis. Aim 1: Mechanistic Discovery (Projects 1 & 2): Determine APOE4 genotype regulation of the perimenopausal bioenergetic, inflammatory and lipid metabolism transitions in brain and their association with Alzheimer's pathology. Determine modulatory factors that reduce or exacerbate the impact of APOE4 genotype. Aim 2: Clinical Translation (Project 3): Determine impact of perimenopause and the APOE4 genotype on brain metabolism, burden of Alzheimer's pathology, structural integrity and cognitive function in perimenopausal and postmenopausal women. Extend analyses of ELITE cohort (600 postmenopausal women) to determine impact of APOE4 genotype on metabolic cluster membership and longitudinal cognitive function. Aim 3: Global Population Translation (Project 3): Determine the impact of APOE4 genotype and menopause on the lifespan trajectories of 5000 women from 10,000+ MRI derived brain volume metrics, genetics and clinical data available through the ENIGMA network. ENIGMA data from 33,195 subjects (women and men) with MRIs and genome sequences will be investigated using a meta-regression model for the effect of age and APOE4 on brain atrophy. Outcomes of our research will provide insights into the mechanisms underlying the heightened risk of AD in APOE4 positive females and identify potential therapeutic targets and opportunities. Studies address NIA Strategic Goals A, C, D and E.